Back to EveryPatent.com
United States Patent |
5,155,127
|
Trivedi
|
October 13, 1992
|
N-(substituted aryl)-N'-(substituted alkoxy)-ureas and thioureas as
antihypercholesterolemic and antiatherosclerotic agents
Abstract
Novel N-[substituted aryl]-N'-(substituted alkoxy)-urea and thiourea
derivatives are described, as well as methods for the preparation and
pharmaceutical composition of same, which are useful in preventing the
intestinal absorption of cholesterol and thus are useful in the treatment
of hypercholesterolemia and atherosclerosis.
Inventors:
|
Trivedi; Bharat K. (Canton, MI)
|
Assignee:
|
Warner-Lambert Company (Morris Plains, NJ)
|
Appl. No.:
|
462563 |
Filed:
|
January 18, 1990 |
Current U.S. Class: |
514/456; 514/457; 514/459; 514/507; 549/399; 549/404; 549/406; 549/407; 560/313; 564/26; 564/27; 564/29; 564/48 |
Intern'l Class: |
A61K 031/35; A61K 031/215; C07D 311/04; C07C 239/00 |
Field of Search: |
549/406,399,407,404
514/459,507,456,457
564/27,29,26,48
560/313
|
References Cited
U.S. Patent Documents
4882353 | Nov., 1989 | Niewohner et al. | 549/406.
|
Primary Examiner: Lee; Mary C.
Assistant Examiner: Whittenbaugh; Robert C.
Attorney, Agent or Firm: Tinney; Francis J.
Parent Case Text
This is a continuation-in-part of United States application Ser. No.
07/308,911, filed Feb. 9, 1989, issued as U.S. Pat. No. 4,923,896 on May
8, 1990.
Claims
I claim:
1. A compound of Formula I
##STR14##
wherein R is phenyl trisubstituted with fluorine, or alkoxy of from one to
four carbon atoms;
X is O or S;
R.sub.1 is hydrogen,
alkyl for from four to sixteen carbon atoms, or phenylalkyl wherein alkyl
is from one to four carbon atoms or when R.sub.1 is alkyl of from nine to
sixteen carbon atoms R is additionally phenyl,
phenyl mono or disubstituted with alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms, fluorine, chlorine, bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms,
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms, alkoxy of
from one to four carbon atoms, fluorine, chlorine, bromine, iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is a defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above;
n is 0 or an integer of 1 or 2;
R.sub.2 is bicyclo[2.2.1]heptane, bicyclo[2.2.1]octane,
##STR15##
wherein n' is an integer of 2 to 6 and R.sub.a is phenyl,
phenyl mono or disubstituted with alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms, fluorine, chlorine, bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms,
phenyl trisubstituted with fluorine, or alkoxy or from one to four carbon
atoms,
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms, alkoxy of
from one to four carbon atoms, fluorine, chlorine, bromine, iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above,
##STR16##
wherein R.sub.6 is hydrogen, alkyl of from one to eight carbon atoms or
phenyl, R.sub.7 is alkyl of from one to eight carbon atoms when R.sub.8 is
alkyl of from one to eight carbon atoms or R.sub.7 is phenyl, and R.sub.8
is phenyl or phenyl substituted with alkyl of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, fluorine, chlorine,
bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above, or when
n is 0 and R.sub.1 is alkyl of from four to sixteen carbon atoms R.sub.6
and R.sub.7 are hydrogen and R.sub.8 is as defined above,
##STR17##
wherein R.sub.9 and R.sub.10 are independently hydrogen, alkyl of from one
to four carbon atoms, alkoxy for from one to four carbon atoms, fluorine,
chlorine, bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is a defined
above or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined
above, and A is 0, or when A is O, and R.sub.1 is hydrogen, alkyl of from
four to eight carbon atoms or phenylalkyl wherein alkyl is from one to
four carbon atoms and X and n are as defined above R is additionally
phenyl, phenyl mono or disubstituted with
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms.
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms, fluorine, chlorine, bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above,
naphthyl or
naphthyl substituted with alkyl of from one to four carbon atoms, alkoxy of
from one to four carbon atoms, fluorine, chlorine, bromine, iodine
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or NR.sub.4 R.sub.5
wherein R.sub.4 and R.sub.5 are as defined above; or a pharmaceutically
acceptable acid addition salt thereof.
2. A compound as defined in claim 1 wherein R.sub.1 is hydrogen or alkyl of
from four to sixteen carbon atoms and R.sub.2 is
##STR18##
wherein n' is an integer of 2 to 6 and R.sub.a is phenyl, phenyl mono or
disubstituted with alkyl of from one to four carbon atoms, alkoxy of from
one to four carbon atoms, fluorine, chlorine, bromine, iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms,
phenyl trisubstituted with fluorine, or alkoxy of from one to four carbon
atoms,
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms, alkoxy of
from one to four carbon atoms, fluorine, chlorine, bromine, iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is a defined above, or NR.sub.4 R.sub.5
wherein R.sub.4 and R.sub.5 are as defined above,
##STR19##
where R.sub.6 is hydrogen, alkyl of from one to eight carbon atoms or
phenyl, R.sub.7 is alkyl of from one to eight carbon atoms wherein R.sub.6
is alkyl of from one to eight carbon atoms or R.sub.7 is phenyl, and
R.sub.8 is phenyl or phenyl substituted with alkyl of from one to four
carbon atoms, alkoxy of from one to four carbon atoms, fluorine, chlorine,
bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above, or when
n is 0 and R.sub.1 is alkyl of from four to sixteen carbon atoms R.sub.6
and R.sub.7 are hydrogen and R.sub.8 is as defined above, or naphthyl.
3. A compound as defined in claim 2 wherein X is 0.
4. A compound as defined in claim 1 having the name
N'-[2,6-bis(1-methylethyl)phenyl]-N-decyl-N-(phenylmethoxy)-urea.
5. A method of treating hypercholesterolemia or atherosclerosis comprising
administering to a mammal in need of such treatment an acylcoenzyme A:
cholesterol acyltransferase-inhibitory effective amount of a compound as
defined in claim 1 in unit dosage form.
6. A pharmaceutical composition for treating hypercholesterolemia or
atherosclerosis comprising an acyl-coenzyme A: cholesterol
acyltransferase-inhibitory effective amount of a compound as defined in
claim 1 in combination with a pharmaceutically acceptable carrier.
Description
BACKGROUND OF THE INVENTION
The present invention relates to novel N-[substituted aryl]-N'-(substituted
alkoxy)-urea and thiourea derivatives useful as pharmaceutical agents, to
methods for their production, to pharmaceutical compositions which include
these compounds, and a pharmaceutically acceptable carrier, and to
pharmaceutical methods of treatment. More particularly, the novel
compounds of the present invention prevent the intestinal absorption of
cholesterol in mammals by inhibiting the enzyme acyl-coenzyme A
(Acyl-CoA):cholesterol acyltransferase (ACAT).
The atheromatous plaque, which is the characteristic lesion of
atherosclerosis, results from deposition of plasma lipids, mainly
cholesteryl esters, in the intima of the arterial wall. Progressive
enlargement of the plaque leads to arterial constriction and ultimately
coronary heart disease. A number of clinical trials have shown a causal
relationship between hypercholesterolemia and coronary heart disease.
Agents that control dietary cholesterol absorption moderate serum
cholesterol levels. Dietary cholesterol is absorbed from the intestinal
lumen as free cholesterol which must be esterified with fatty acids. This
reaction is catalyzed by the enzyme acyl-CoA: cholesterol acyltransferase
(ACAT). The resulting cholesteryl esters are packaged into the
chylomicrons which are secreted into the lymph. Inhibitors of ACAT not
only prevent absorption of dietary cholesterol but also prevent the
reabsorption of cholesterol which has been released into the intestine
through endogenous regulatory mechanisms, thus lowering serum cholesterol
levels and ultimately counteracting the formation or development of
atherosclerosis.
Copending United States Ser. No. 147,037, filed Feb. 5, 1988 now abandoned,
describes certain substituted urea, thiourea, carbamate, and thiocarbamate
compounds as potent ACAT inhibitors.
Copending United States Ser. No. 176,079, filed Mar. 30, 1988 now U.S. Pat.
No. 5,116,848, describes certain
N-[[(2,6-disubstituted)phenyl]-N'-diarylalkyl]ureas as potent ACAT
inhibitors.
Copending United States Ser. No. 175,089, filed Mar. 30, 1988 now
abandoned, describes certain
N-[[2,6-disubstituted)phenyl]-N'-arylalkyl]ureas as potent ACAT
inhibitors.
Copending United States Ser. No. 176,080, filed Mar. 30, 1988, describes
certain N-2,6-dialkyl or N-2,6-dialkoxyphenyl-N'-arylalkylurea compounds
as potent ACAT inhibitors.
However, the compounds disclosed in the aforementioned copending United
States applications do not suggest or disclose the combination of
structural variations of the compounds of the present invention described
hereinafter.
SUMMARY OF THE INVENTION
Accordingly, the present invention is a novel class of compounds of Formula
I
##STR1##
wherein R is phenyl, phenyl mono or disubstituted with
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms,
phenyl trisubstituted with fluorine, or alkoxy of from one to four carbon
atoms,
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above;
X is O or S;
R.sub.1 is hydrogen, alkyl of from four to sixteen carbon atoms, or
phenylalkyl wherein alkyl is from one to four carbon atoms;
n is 0 or an integer of 1 or 2;
R.sub.2 is bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
##STR2##
wherein n' is an integer of 2 to 6 and R.sub.a is as defined above,
##STR3##
wherein R.sub.6 is hydrogen, alkyl of from one to eight carbon atoms or
phenyl, R.sub.7 is alkyl of from one to eight carbon atoms when R.sub.6 is
alkyl of from one to eight carbon atoms or R.sub.7 is phenyl, and R.sub.8
is phenyl or phenyl substituted with alkyl of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, fluorine, chlorine,
bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above, or when
n is 0 and R.sub.1 is alkyl of from four to sixteen carbon atoms R.sub.6
and R.sub.7 are hydrogen and R.sub.8 is as defined above,
##STR4##
wherein R.sub.9 and R.sub.10 are independently hydrogen, alkyl of from one
to four carbon atoms, alkoxy of from one to four carbon atoms, fluorine,
chlorine, bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined
above or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined
above, and A is 0, S, SO, SO.sub.2, or --CH.sub.2 --,
naphthyl or
naphthyl substituted with alkyl of from one to
four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above; or a
pharmaceutically acceptable acid addition salt thereof.
Additionally, the present invention is directed to a novel method of
treating hypercholesterolemia or atherosclerosis comprising administering
to a mammal in need of such treatment an acyl-coenzyme A:cholesterol
acyltransferase-inhibitory effective amount of a compound of Formula I in
unit dosage form.
Also, the present invention is directed to a pharmaceutical composition for
treating hypercholesterolemia or atherosclerosis comprising an
acyl-coenzyme A:cholesterol acyl transferase-inhibitory effective amount
of a compound of Formula I in combination with a pharmaceutically
acceptable carrier.
Finally, the present invention is directed to methods for production of a
compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of Formula I, the term "alkyl" means a straight or
branched hydrocarbon radical having from one to eight carbon atoms and
includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tertiary-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,
n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,
and the like.
"Alkoxy" is O-alkyl in which alkyl is as defined above.
Certain of the compounds of Formula I are capable of further forming
pharmaceutically acceptable acid addition salts. Both of these forms are
within the scope of the present invention. Pharmaceutically acceptable
acid addition salts are formed with inorganic and organic acids, such as,
for example, hydrochloric, sulfuric, phosphoric, acetic, citric, guconic,
fumaric, methanesulfonic, and the like (see, for example, Berge, S. M., et
al, "Pharmaceutical Sats", Journal of Pharmaceutical Science, 66, pp. 1-19
(1977)). The acid addition salts of said basic compounds are prepared by
contacting the free base form with a sufficient amount of the desired acid
to produce the salt in the conventional manner. The free base form may be
regenerated by contacting the salt form with a base and isolating the free
base in the conventional manner. The free base forms differ from their
respective salt forms somewhat in certain physical properties such as
solubility in polar solvents, but otherwise the salts are equivalent to
their respective free base for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated
forms as well as solvated forms, including hydrated forms. In general, the
solvated forms, including hydrated forms, are equivalent to unsolvated
forms and are intended to be encompassed within the scope of the present
invention.
Certain of the compounds of the present invention possess asymmetric carbon
atoms (optical centers), the racemates as well as the individual
enantiomers are intended to be encompassed within the scope of the present
invention.
A preferred compound of Formula I is one wherein R.sub.1 is hydrogen or
alkyl of from four to sixteen carbon atoms and R.sub.2 is
##STR5##
wherein n' is an integer of 2 to 6 and R.sub.a is phenyl,
phenyl mono or disubstituted with
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms,
phenyl trisubstituted with fluorine, or alkoxy of from one to four carbon
atoms,
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above,
##STR6##
where R.sub.6 is hydrogen, alkyl of from one to eight carbon atoms or
phenyl, R.sub.7 is alkyl or from one to eight carbon atoms when R.sub.6 is
alkyl of from one to eight carbon atoms or R.sub.7 is phenyl, and R.sub.8
is phenyl or phenyl substituted with alkyl of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, fluorine, chlorine,
bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above, or when
n is 0 and R.sub.1 is alkyl of from four to sixteen carbon atoms R.sub.6
and R.sub.7 are hydrogen and R.sub.8 is as defined above, or naphthyl.
Another preferred embodiment is a compound of Formula I wherein X is 0 .
Particularly valuable are:
N-[2,6-Bis(1-methylethyl)phenyl]-N'-(diphenylmethoxy)-urea;
N-[2,6-Bis(1-methylethyl)phenyl]-N'-(triphenylmethoxy)-urea;
N-[2,6-Bis(1-methylethyl)phenyl]-N'-(1-naphthenylmethoxy)-urea; and
N'-[2,6-Bis(1-methyethyl)phenyl]-N-decyl-N-(phenylmethoxy)-urea; or a
pharmaceutically acceptable acid addition salt thereof.
The compounds of the present invention are potent inhibitors of the enzyme
acyl-CoA:cholesteryl acyltransferase (ACAT), and are thus effective in
inhibiting the esterification and transport of cholesterol across the
intestinal cell wall. Thus, the compounds of the present invention are
useful in pharmaceutical formulations for the inhibition of intestinal
absorption of dietary cholesterol, the reabsorption of cholesterol
released into the intestine by normal body action, or the modulation of
cholesterol.
The ability of representative compounds of the present invention to inhibit
ACAT was measured using an in vitro test more fully described in Field, F.
J. and Salome, R. G., Biochimica et Biophysica Acta, volume 712, pages
557-570 (1982). The test assesses the ability of a test compound to
inhibit the acylation of cholesterol by oleic acid by measuring the amount
of radio-labeled cholesterol oleate formed from radio-labeled oleic acid
in a tissue preparation containing rabbit intestinal microsomes. The data
in Table I is expressed as IC.sub.50 values, i.e., the concentration of
test compound required to inhibit cholesteryl oleate formation to 50% of
control. The data in the table shows the ability of representative
compounds of the present invention to potently inhibit ACAT.
TABLE 1
______________________________________
Biological Activity of Compounds of Formula I
Example IC.sub.50
Number Compound (.mu. moles)
______________________________________
1 N-[2,6-Bis(1-methylethyl)phenyl]-
0.030
N'-(diphenylmethoxy)-urea
2 N-[2,6-Bis(1-methylethyl)phenyl]-
0.053
N'-(triphenylmethoxy)-urea
3 N-[2,6-Bis(1-methylethyl)phenyl]-
0.092
N'-(1-naphthalenylmethoxy)-urea
______________________________________
A compound of Formula I
##STR7##
wherein R is phenyl, phenyl mono or disubstituted with
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is alkyl of from one to four carbon atoms,
or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or
alkyl of from one to four carbon atoms,
phenyl trisubstituted with fluorine, or alkoxy of from one to four carbon
atoms,
naphthyl, or
naphthyl substituted with alkyl of from one to four carbon atoms alkoxy of
from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above;
X is O or S;
R.sub.1 is hydrogen, alkyl of from four to sixteen carbon atoms, or
phenylalkyl wherein alkyl is from one to four carbon atoms;
n is 0 or an integer of 1 or 2;
R.sub.2 is bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
##STR8##
wherein n' is an integer of 2 to 6 and R is as defined above,
##STR9##
wherein R.sub.6 is hydrogen, alkyl of from one to eight carbon atoms or
phenyl, R.sub.7 is alkyl of from one to eight carbon atoms when R.sub.6 is
alkyl of from one to eight carbon atoms or R.sub.7 is phenyl, and R.sub.8
is phenyl or phenyl substituted with alkyl of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, fluorine, chlorine,
bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above, or when
n is 0 and R.sub.1 is alkyl of from four to sixteen carbon atoms R.sub.6
and R.sub.7 are hydrogen and R.sub.8 is as defined above,
##STR10##
wherein R.sub.9 and R.sub.10 are independently hydrogen, alkyl of from one
to four carbon atoms, alkoxy of from one to four carbon atoms, fluorine,
chlorine, bromine, iodine, CO.sub.2 R.sub.3 wherein R.sub.3 is as defined
above or NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined
above, and A is 0, S, SO, SO.sub.2, or --CH.sub.2 --,
naphthyl or
naphthyl substituted with alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
fluorine,
chlorine,
bromine,
iodine,
CO.sub.2 R.sub.3 wherein R.sub.3 is as defined above, or
NR.sub.4 R.sub.5 wherein R.sub.4 and R.sub.5 are as defined above; or a
pharmaceutically acceptable acid addition salt thereof is prepared by
reacting a compound of Formula II
##STR11##
wherein R.sub.1, R.sub.2, and n are as defined above with a compound of
Formula III
R--N.dbd.C.dbd.X III
wherein R and X are as defined above in a solvent such as, for example,
ethyl acetate and the like to give a compound of Formula I.
A compound of Formula IIb
##STR12##
wherein R.sub.11 is alkyl of from four to sixteen carbon atoms or
phenylalkyl wherein alkyl is from one to four carbon atoms and R.sub.2 and
n are as defined above, is prepared by reacting a compound of Formula IIa
H.sub.2 N--O--(CH.sub.2).sub.n --R.sub.2 IIa
wherein R.sub.2 and n are as defined above with a compound of Formula IV
R.sub.11 --HAL IV
wherein HAL is bromine or chlorine and R.sub.11 is as defined above in the
presence of a base such as, for example, sodium hydroxide, sodium
carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate,
potassium bicarbonate, and the like to give a compound of Formula IIb.
Additionally, a compound of Formula Ia
##STR13##
wherein R.sub.11 is alkyl of from four to sixteen carbon atoms or
phenylalkyl wherein alkyl is from one to four carbon atoms and R, R.sub.2,
X, and n are as defined above may be prepared by reacting a compound of
Formula I wherein R.sub.1 is hydrogen and R, R.sub.2, X, and n are as
defined above with a compound of Formula IV and a base such as, for
example, sodium hydride and the like in the presence of a solvent such as,
for example, dimethylformamide and the like using the methodology
described by Sulsky, R. and Demers, J. P., Tetrahedron Letters, Volume 30,
pages 31-34 (1989) to give a compound of Formula Ia.
A compound of Formula IIa is either known or may be prepared using the
methodology described by A. F. McKay, et al., Canadian Journal of
Chemistry, Volume 38, pages 343-358 (1960), E. L. Schumann, et al, Journal
of Medicinal Chemistry, Volume 7, pages 329-334 (1964), and P. Mamalis, et
al, Journal of the Chemical Society, pages 229-238 (1960).
A compound of Formula III or Formula IV is either known or capable of being
prepared by methods known in the art.
The compounds of the present invention can be prepared and administered in
a wide variety of oral and parenteral dosage forms. It will be obvious to
those skilled in the art that the following dosage forms may comprise as
the active component, either a compound of Formula I or a corresponding
pharmaceutically acceptable salt of a compound of Formula 1.
For preparing pharmaceutical compositions from the compounds of the present
invention, pharmaceutically acceptable carriers can be either solid or
liquid. Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier can be
one or more substances which may also act as diluents, flavoring agents,
solubilizers, lubricants, suspending agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture
with the finely divided active component.
In tablets, the active compound is mixed with the carrier having the
necessary binding properties in suitable proportions and compacted in the
shape and size desired.
The powders and tablets preferably contain from five or ten to about
seventy percent of the active compound. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,
starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The
term "preparation" is intended to include the formulation of the active
compound with encapsulating material as a carrier providing a capsule in
which the active component, with or without other carriers, is surrounded
by a carrier, which is thus in association with it. Similarly, cachets and
lozenges are included. Tablets, powders, capsules, pills, cachets, and
lozenges can be used as solid dosage forms suitable for oral
administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty
acid glycerides or cocoa butter, is first melted and the active component
is dispersed homogeneously therein, as by stirring. The molten homogeneous
mixture is then poured into convenient sized molds, allowed to cool, and
thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for
example, water or water propylene glycol solutions. For parenteral
injection liquid preparations can be formulated in solution in aqueous
polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the
active component in water and adding suitable colorants, flavors,
stabilizing and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the
finely divided active component in water with viscous material, such as
natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be
converted, shortly before use to liquid form preparations for oral
administration. Such liquid forms include solutions, suspensions, and
emulsions. These preparations may contain, in addition to the active
component, colorants, flavors, stabilizers, buffers, artificial and
natural sweeteners, dispersants, thickeners, solubilizing agents, and the
like.
The pharmaceutical preparation is preferably in unit dosage form. In such
form, the preparation is subdivided into unit doses containing appropriate
quantities of the active component. The unit dosage form can be a packaged
preparation, the package containing discret quantities of preparation,
such as packeted tablets, capsules, and powders in vials or ampoules.
Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge
itself, or it can be the appropriate number of any of these in packaged
form.
The quantity of active component in a unit dose preparation may be varied
or adjusted from 50 mg to 1500 mg preferably 200 mg to 500 mg according to
the particular application and the potency of the active component. The
composition can, if desired, also contain other compatible therapeutic
agents.
The dosage range for a 70-kg mammal is from about 1 mg/kg to about 100
mg/kg of body weight per day or preferably about 3 mg/kg to about 15 mg/kg
of body weight per day when the compounds of the present invention are
used therapeutically as antihypercholesterolemic and antiatherosclerotic
agents. The dosages, however, may be varied depending upon the
requirements of the patient, the severity of the condition being treated,
and the compound being employed. Determination of the proper dosage for a
particular situation is within the skill of the art. Generally, treatment
is initiated with smaller dosages which are less than the optimum dose of
the compound. Thereafter, the dosage is increased by small increments
until the optimum effect under the circumstances is reached. For
convenience, the total daily dosage may be divided and administered in
portions during the day if desired.
The following nonlimiting examples illustrate the inventor's preferred
methods for preparing the compounds of the invention.
EXAMPLE 1
N-[2,6-Bis(1-methylethyl)phenyl]-N'-(diphenylmethoxy)-urea
To a solution of 1,1-diphenylmethoxyamine (0.9 g, 0.0045 mol) (E. L.
Schumann, et al, Journal of Medicinal Chemistry, Volume 7, pages 329-334
(1964)) in 20 ml of ethyl acetate is added 2,6-diisopropylphenyl
isocyanate (0.91 g, 0.0045 mol) and the reaction mixture is stirred for 20
hours at room temperature. The volatiles are removed under reduced
pressure and the residue treated with 30 ml hexane-ethyl acetate (4:1).
The precipitated solid is filtered and dried affording 1.45 g of
N-[2,6-bis(1-methylethyl)phenyl]-N'-(diphenylmethoxy)-urea; mp
152.degree.-154.degree. C.
In a process analogous to Example 1 using appropriate starting materials,
the corresponding compounds of Formula I are prepared:
EXAMPLE 2
N-[2,6-Bis(1-methylethyl)phenyl]-N'-(triphenylmethoxy)urea; mp
198.degree.-200.degree. C.
EXAMPLE 3
N-[2,6-Bis(1-methylethyl)phenyl]-N'-(1-naphthalenylmethoxy)-urea; mp
128.degree.-130.degree. C.
EXAMPLE 4
N'-[2,6-Bis(1-methylethyl)phenyl]-N-decyl-N-(phenylmethoxy)-urea
STEP A: Preparation of
N-[2,6-Bis(1-methylethyl)-phenyl]-N'-(phenylmethoxy)-urea
O-Benzylhydroxylamine is prepared by adding 6 g of O-benzylhydroxylamine
hydrochloride to 50 ml of a 25% solution of sodium hydroxide in water and
extracting with ethyl acetate (3.times.100 ml). The combined ethyl acetate
extracts are washed with water and dried over magnesium sulfate. The
colorless oil which remained after filtration and concentration (3.4 g,
27.6 mmol) is dissolved in 25 ml of ethyl acetate and 6 ml of
2,6-diisopropylphenyl isocyanate (90%) in 5 ml of ethyl acetate is added
dropwise under nitrogen. The mixture is stirred overnight at room
temperature, filtered, concentrated and the solid residue triturated with
isopropyl ether. Filtration afforded 5.24 g of
N-[2,6-bis(1-methylethyl)phenyl]-N'-(phenylmethoxy)-urea as a colorless
solid; mp 136.degree.-138.degree. C. A second crop of 3.9 g is also
isolated; mp 136.degree.-138.degree. C.
STEP B: Preparation of
N'-[2,6-Bis(1-methylethyl)-phenyl]-N-decyl-N-(phenylmethoxy)-urea
A solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-(phenylmethoxy)-urea
(1.62 g, 5 mmol) in 5 ml of dry dimethylformamide is added dropwise to a
room temperature suspension of hexane washed sodium hydride (0.13 g, 5.5
mmol) in 3 ml of dry dimethylformamide with stirring. When gas evolution
is complete, the suspension is warmed to 60.degree. C. and 1-bromodecane
(1 ml, 5 mmol) is added dropwise. The mixture is stirred for 30 minutes,
cooled to room temperature, poured into water and extracted with diethyl
ether. The diethyl ether extract is diluted with hexane and washed with
water, dried, filtered, and evaporated to provide a colorless solid which
is triturated with hexane to give 1.47 g of
N'-[2,6-bis(1-methylethyl)phenyl]-N-decyl-N-(phenylmethoxy)-urea; mp
91.degree.-93.degree. C.
Top